White Coat Underground

Endocrine disruptors—the one true cause?

A common theme in alternative medicine is the “One True Cause of All Disease”. Aside from the pitiable naivete, it’s implausible that “acidic diet”, liver flukes, colonic debris, the Lyme spirochete, or any other problem—real or imagined—can cause “all disease” (in addition to the fact that most of these ideas are intrinsically mutually exclusive).

One of the popular new ideas in this category is that of “endocrine disrupting chemicals” (EDCs). These are chemicals in the environment that physiologically or chemically mimic naturally occurring human hormones. That some environmental substances are chemically similar to human hormones is indisputable. That these substances can have a real physiologic effect in vitro seems to hold up. How much of an effect these chemicals may have in real human populations is an open question.

And unlike many similar ideas, there are a lot of plausible questions that are under investigation. And this is where I fear our colleagues in the media lose it. The media can be an effective source of public health information, even a tool to improve public health, but when the media unleashes a torrent of premature speculation, science and the public health lose. This is where the Times’s Nicholas Kristoff comes in. On Sunday, he asked these questions:

The battle over health care focuses on access to insurance, or tempests like the one that erupted over new mammogram guidelines.

But what about broader public health challenges? What if breast cancer in the United States has less to do with insurance or mammograms and more to do with contaminants in our water or air — or in certain plastic containers in our kitchens? What if the surge in asthma and childhood leukemia reflect, in part, the poisons we impose upon ourselves?

We have many examples of human-made environmental chemicals causing disease. Often, a cluster of disease is identified, and then a common exposure is found, and further study confirms a likely causal relationship. For example, in the 20th century, thousands of people in Minamata, Japan fell ill and died from a mysterious neurological ailment. Investigation found that industrial methyl mercury contamination had entered the seafood chain and was the responsible agent.

Conversely, suspect contaminated regions can be identified, and then clusters of disease can be sought. This is a bit trickier, but still a legitimate way of investigating a relationship. The Michigan PBB incident in one such example in which health effects were hard to nail down. Cigarette smoking as a cause of cancer was a bit more clear.

A less effective way to approach this type of problem is to have neither a clear disease cluster nor a clear exposure group. This is the mistake made by Kristoff. He relates EDCs to several problems, but focuses on breast cancer, drawing a line from EDCs to early puberty, to longer time from menarche to menopause, to increased breast cancer rates. While this is not implausible, it’s pretty damned tenuous. In order to see if EDCs are really causing breast cancer in significant numbers, we should establish both a correlation between exposure to specific chemicals and excess cases of breast cancer. We should also have a laboratory model for the connection.

The problem here from a science-based medicine perspective is not the implausibility but the oversimplification and naive, hyperbolic conclusions. Kristoff cites a 56-page report from the Endocrine Society, which was much more circumspect and called for further study of the issue. I can understand the desire to communicate an important health story to the public, but choosing an emotionally charged issue like breast cancer and linking it to everyday substances that everyone uses blurs the issue more than it clarifies. It incites emotion without asking clear, important questions.

When I’ve talked to experienced public health experts about EDCs, they’ve given me a noncommittal, “yeah, there could be something to that,” but none that I’ve read have been willing to call this a major public health threat. We know the causes of lots of cancers. We know how to screen for many important cancers, which allows for early detection and treatment. Some cancers we can actually prevent by limiting environmental exposures; many lung cancers could be prevented by eliminating exposure to cigarette smoke. Whether any cancers can be prevented by banning putative EDCs is a question that’s barely been asked, much less answered.

Comments

  1. #1 History Punk
    December 7, 2009

    So you’re say that isn’t one diagnosis them to rule them all.
    Besides, if physicists have the Theory of Everything, doesn’t that by some tortured logic that I am incapable of pondering or recreating, mean that their theory of everything of the body is accurate too?

  2. #2 WMDKitty
    December 7, 2009

    I have no clue what’s going on — what’s the plain-english version?

  3. #3 daedalus2u
    December 7, 2009

    History Punk, there is one compound that rules them all, that compound is nitric oxide.

    All of the steroid hormones and many of the other ones are synthesized using the cytochrome P450 enzymes. Those enzymes are actively regulated by NO. NO binds to the heme and prevents O2 from binding. The synthesis of testosterone in particular is regulated by NO. Low NO increases androgen levels. Increased androgen levels increase the growth of pubic hair. Expanded pubic hair increases the niche for the bacteria I am working with so they produce more NO/NOx which is absorbed and (my hypothesis) increases NO levels and decreases androgen levels. Since I raised my NO level I have experienced (I think) a slight reduction in androgen levels, my male pattern baldness regressed ever so slightly, and my skeletal muscle mass decreased a little bit too. Maybe I am just getting old and weak, but maybe not.

    The NO level is already regulating the P450 enzymes. A change in the NO level will affect those enzymes with no threshold because the NO level is already in the “active range”, that is the range where it is already regulating steroid synthesis. Steroid synthesis is complex, there are a lot of enzymes, a lot of compounds are both products and substrates for different enzymes. I think that low NO triggers “stress response” pathways, and it is these pathways that cause people to grow faster, become bigger, mature sooner, and put on biomass with greater efficiency; the same things that antibiotics do to farm animals. I suspect the final common pathway is the same, a perturbation of NO/NOx physiology in the low direction.

    The decline in the age of menarche parallels the advent of bathing better than it does the advent of xenobiotic chemicals. The NYT article says it was 17 in the 1800’s and dropped to 14 by 1900. They didn’t have PCBs or DDT in 1900. They did have the germ theory, soap and the aphorism that “cleanliness is next to Godliness”. Maybe what we need is some 21st century atheist skepticism.

  4. #4 mizz.lee
    December 7, 2009

    The phenomenon of earlier menarche has been causally related to changes in diet, actually. Menarche requires a threshold level of body fat, which has been increasingly easy to meet at a young age given our calorie-dense and plentiful diets. Even within a generation, young girls with higher body fat reach menarche earlier than do thinner girls.

    Daedalus2u, I’m not sure what you’re trying to say about bathing…that it’s equally spurious?

  5. #5 Isis the Scientist
    December 7, 2009

    I think Kristof may be saying something more similar to what you are. When I read his article, which I linked to myself, I took away that these toxins/pollutants may be important here and that there is a trend worth considering based on some key preliminary evidence.

    But, I think that you are right in one major way — a good scientist does not come to a final conclusion based on preliminary evidence. What I wondered about today was whether we were making a major recommendation when there are still so many questions to ask.

  6. #6 daedalus2u
    December 7, 2009

    mizz.lee, I have just published a paper in a book on the hygiene hypothesis that suggests that bathing may be one of the causal factors due to the removal of ammonia oxidizing bacteria on the skin. My research indicates that these bacteria set the basal NO level and because all NO pathways only “sense” the sum of NO from all sources, including the basal level, a change in that basal level affects all NO pathways with no threshold.

    What is the mechanism for antibiotics affecting the growth rate, time to maturity and feed efficiency in farm animals? The mechanism is not known. I think it is low NO causing endocrine disruption, making farm animals hyperandrogenic, making them grow big and fat and mature sooner. The same thing that bathing did to humans.

  7. #7 Isis the Scientist
    December 7, 2009

    Daedalus, I love you and your hypotheses, but after reading your last comment I can only imagine .

    I’m trying to be a grown-up. I am.

  8. #8 Isis the Scientist
    December 7, 2009

    Oops, I meant I can only imagine this.

  9. #9 Kim
    December 7, 2009

    It will be interesting to see how the endocrine disruptor thing turns out, but I think in the culture at the moment it’s often used as a diversion: “nevermind the habits I know are unhealthy, all I need to do is eliminate all these BPA-containing water bottles!”

    Maybe it will turn out that endocrine disrupting chemicals contribute to breast cancer and who knows what else…but we *know* that obesity and type 2 diabetes are linked to cancers and other things that’ll kill you.

  10. #10 BB
    December 8, 2009

    And of course Kristoff totally igonored lifestyle and nutritional differences. Menarche was already earlier than 17 in the late 1960′s and early 1970′s, long before the bottled water craze. And considering how many young women were married at 16 or 17 centuries ago, I have to wonder if menarche ever started as late on average as Kristoff maintained in the article. Pre-pubescent girls can’t be married; they may be barren always, so people would have thought.

    One more thought: our lab animals (and small pets) have been switched from glass bottles to plastic bottles over the years (this is going acorss several institutions). Wonder if anyone has looked at fetility data or spontaneous tumor data on cohorts of mice, hamsters, etc., to see if there were any differences post-switch.

  11. #11 James Sweet
    December 8, 2009

    So you say it’s an “open question” how much effect these things can have in human populations… do you have a gut feeling for it?

    My wife has decided that we are now avoiding BPA, which is a major pain in the ass (though it does mean I’ll finally have a strong incentive to can my own tomatoes next season, something I’ve been meaning to do for a while now anyway). I’m skeptical about how much of an effect it could be having, but she is convinced. (There are some legitimate scientists at University of Rochester who seem to think it’s a really terrible thing… Not that the opinion of one team of legitimate scientists gets to decide reality, but when you are a new mom, one team of legitimate scientists crying “Danger!” is enough to tip the scales. At least she’s not listening to quacks — I saw on a parenting mailing list she is on that some lady is using chiropractic to treat her child’s lazy eye, because she doesn’t want to use “medical stuff” like an eye patch! Hmmm, neglect? Anyway, I significantly digress…)

    So… how does PalMD feel about EDCs? Worth cutting back on out of an abundance of caution, given the preliminary results in the literature? Or just another altie paranoia?

  12. #12 PalMD
    December 8, 2009

    At this point, my family has decided to try to avoid BPA and to keep an eye on the evidence so that we can make informed decisions. There is no way to avoid every putative EDC at this point and it is not clear whether it would be worth it.

  13. #13 Dianne
    December 8, 2009

    Isis: I couldn’t get your link to work. Given what I’m imagining that you might be imagining, that may be just as well.

  14. #14 daedalus2u
    December 8, 2009

    It should be pointed out that there are plenty of “natural” endocrine disrupters. There are lots of estrogen-like compounds in many plants, wheat germ for example, yams and soy.

    Plants and animals have endocrine systems too, and they generate compounds to regulate those systems and many of those compounds are cross-reactive with human endocrine systems. When we eat those plants and animals we also consume the compounds they generate to regulate their endocrine systems.

    There is probably some tolerance for consuming EDCs because of the unavoidability of them in food. But evolving resistance to particular EDCs likely takes significant evolutionary time while the individuals not resistant to those EDCs experience reduced reproductive success.

    Agriculture is recent enough that even for common stable foods there may not be complete resistance to EDCs in them. I would expect that individuals would be more resistant to the EDCs in their ethnic groups “traditional” foods than to foods from distant regions. For example soy has been used as food in China for more than 5,000 years. I would expect that those of Asian descent to be more resistant to the phytoestrogens in soy than those of European, African or Native American descent. Perhaps that exposure to the phytoestrogens in soy over a few hundred generations in Asia is what is responsible for part of the differential incidence of breast cancer in Asian women compared to other ethnic groups.

  15. #15 Kim
    December 8, 2009

    Most parents I know are avoiding BPA. I think I would, too, if I had kids. Since I don’t, I kind of can’t be bothered. It’s going to phase out of the market in time in any case, now that there’s so much market pressure to get rid of it.

  16. #16 Mu
    December 8, 2009

    I love people telling me they are avoiding BPA. That stuff is so ubiquitous, it’s not even funny. But then, I also think that the hype over it is ridiculous; I never understood why micromolar amounts are harmless and nanomolar do all kind of weird things to you.

  17. #17 TheDissenter
    December 9, 2009

    For a physician you sure seem to be lazy in your thinking and content to quickly brush past inconvenient truths.

    “For example, in the 20th century, thousands of people in Minamata, Japan fell ill and died from a mysterious neurological ailment.”

    It took 30 YEARS for physicians to figure out what was going on, and it happened yet again years later. I wonder how many of those people were told by their physician that they were fine, and its all in their head? 30 years from now, physicians might finally understand the implications of BPA, who is to say? I am guessing that had you been working in Japan in the ’50s you would have been one of the dismissive doctors brushing the inconvenient truth of mercury poisoning under the rug leaving thousands to suffer and die a horrible death to save you the work of perhaps thinking outside your little medical box and actually having to, God forbid, question your sacrosanct assumptions. No, doctors are memorizers, not thinkers.

    “Aside from the pitiable naivete, it’s implausible that “acidic diet”, liver flukes, colonic debris, the Lyme spirochete, or any other problem—real or imagined—can cause “all disease” (in addition to the fact that most of these ideas are intrinsically mutually exclusive).”

    I don’t recall reading anywhere that “alternative medicine” claims one thing causes all disease. Sounds like a straw man argument to me, and a poor one at that. Curiously you mention Lyme disease, known along with syphilis, as the great imitator precisely because it can disguise itself as so many other diseases and affects so many of the bodies subsystems. If there was ever an organism that had the potential to be the cause of all disease its borrelia, yet you seem to put it in the category of “imaginary” disease. In fact, Lyme disease is very analogous to Minamata disease, and I won’t be surprised at all if it takes 30 years for physicians to finally figure out what many non-physicians have known about borrelia for years. Oops!

    “The problem here from a science-based medicine perspective…”

    That sentence gave me a good chuckle. You speak for science based medicine do you? Only around 20% of allopathic medicine has any science behind it at all, and we all know about the medical “science” that thought washing your hands to prevent infection was ridiculous, ulcers were caused by spicy foods and stress, thalidomide is safe, smoking cures a sore throat, masturbating will blind you, and on and on. With a record like that it amazes me that doctors aren’t the most humble creatures on earth. No profession has screwed up as much or as badly as medicine causing all manner of misery and death over the centuries and yet you complain about oversimplification and naive, hyperbolic conclusions? In future articles, I would suggest that you try doing less memorizing and more thinking and see what happens.

  18. #18 Dangerous Bacon
    December 9, 2009

    TheDissenter, who chastises PalMD for “lazy thinking” and “inconvenient truths”, says that “It took 30 YEARS for physicians to figure out what was going on (in the Minamata, Japan epidemic of neurological disease).”

    In fact, following the outbreak of the epidemic in 1956 it was concluded by investigators within about six months that heavy metal exposure was to blame, and organic mercury was singled out within three years:

    “On November 12, 1959 the Ministry of Health and Welfare’s Minamata Food Poisoning Subcommittee published its results:

    “Minamata disease is a poisoning disease that affects mainly the central nervous system and is caused by the consumption of large quantities of fish and shellfish living in Minamata Bay and its surroundings, the major causative agent being some sort of organic mercury compound.”

    http://en.wikipedia.org/wiki/Minamata_disease

    TD “I don’t recall reading anywhere that “alternative medicine” claims one thing causes all disease. Sounds like a straw man argument to me, and a poor one at that.”

    Except that you’ve been given a sample of the many things blamed by alties for disease (without good evidence), and there are numerous others (such as Candida) along with a bevy of bogus remedies to allegedly treat the phony causes.

    “Only around 20% of allopathic medicine has any science behind it at all”

    Perhaps you can give us a cite to support this statement? Sounds like the sort of claim that’s bandied up alt med sites and repeated endlessly without evidentiary backing.

    “With a record like that it amazes me that doctors aren’t the most humble creatures on earth.”

    Physicians and scientists are in fact humble enough to know that science-based medicine is constantly being questioned and when appropriate, revamped to accomodate new evidence. It’s alternative medicine promoters who typically circulate dubious theories and sell untested/unproven drugs, then are unwilling to give up their ineffective treatments, hanging on to them indefinitely because they’re uninterested in rigorously testing them, or simply because the ancients thought they had value.

  19. #19 PalMD
    December 9, 2009

    DB, we call it “humility in the face of disease”.

  20. #20 TheDissenter
    January 2, 2010

    “Perhaps you can give us a cite to support this statement?
    Sounds like the sort of claim that’s bandied up alt med sites and repeated endlessly without evidentiary backing.”

    Are you calling the BMJ an “alties” publication? Sounds like you are unfamiliar with your own supposed area of expertise. How sad for your patients…

    “So what can Clinical Evidence tell us about the state of our current knowledge? What proportion of commonly used treatments are supported by good evidence, what proportion should not be used or used only with caution, and how big are the gaps in our knowledge? Of around 2500 treatments covered 13% are rated as beneficial, 23% likely to be beneficial, 8% as trade off between benefits and harms, 6% unlikely to be beneficial, 4% likely to be ineffective or harmful, and 46%, the largest proportion, as unknown effectiveness (see figure 1).”

    http://clinicalevidence.bmj.com/ceweb/about/knowledge.jsp

    20% was generous as you can see.

    “Physicians and scientists are in fact humble enough to know that science-based medicine is constantly being questioned…”

    Its not science-based medicine, its money-based medicine and I haven’t met many humble medical professionals in my day. They are a rare breed indeed.

    “…and when appropriate, revamped to accomodate new evidence.”

    Sure, that’s why the AG of CT had to make the unprecedented move to sue the IDSA to uncover all the conflicts of interests in the diagnosis and treatment guidelines for Lyme disease. The IDSA is the antithesis of humility. Do you have any evidence that supports your assertion? Usually it takes decades for the medical establishment to correct a fundamental flaw in thinking. There are still many physicians out there that don’t believe stomach ulcers can be caused by a bacteria!

    “It’s alternative medicine promoters who typically circulate dubious theories and sell untested/unproven drugs, then are unwilling to give up their ineffective treatments, hanging on to them indefinitely because they’re uninterested in rigorously testing them, or simply because the ancients thought they had value.”

    Any evidence of this? It sounds like the sort of claim that’s bandied about at medical blogs and repeated endlessly without evidence.